This invention relates to systems and methods for screening pharmaceutical chemicals. More in particular, this invention relates to systems and methods for screening pharmaceutical chemicals in tissue models.
The number of pharmaceutical chemicals that must be tested for efficacy has increased enormously, mainly due to the development of large libraries of chemicals obtained using parallel and combinatorial chemical synthesis methods. Correspondingly, the number of identified therapeutic targets such as receptor and intracellular regulatory proteins has greatly increased since the application of functional genomics. Therefore, there is a great need for rapid and quantitative methods with which to screen pharmaceutical chemical(s) for their ability to elicit specific cellular responses and to identify leading pharmaceutical candidates.
Initial screening of large libraries of chemicals is carried out by testing for specific binding to target molecules using assay methods that operate in solution. High throughput methods have been developed based on scintillation proximity assay or fluorescence detection techniques (Sundberg, 2000). These methods, while readily adapted to screen thousands of compounds per day, provide information only about the strength and specificity of chemical interaction, not about cell responses. Hence, chemicals that are initially selected based on their ability to bind to a target in solution must be rescreened to assess their ability to elicit a desired cellular response. These secondary and tertiary levels of screening add increased expense and time to the process of detecting promising or lead pharmaceutical chemicals.
Stimulation of receptors and activation of ion channels have been assessed using fluorescence methods to detect changes in, e.g., calcium ion concentration, membrane potential and pH (Sundberg, 2000). These changes in ion concentration and transport often occur relatively early in the process of signal transduction and lead to more specific end responses such as the activation of specific enzymes. Hence, measurement of these responses does not necessarily provide information about the ultimate cellular responses that are activated or inhibited by a test pharmaceutical compound.